Therapy Sequencing Strategies in Multiple Myeloma: Who, What and Why?

Abstract

The past decade has witnessed a boom in the therapeutic landscape for the management of multiple myeloma. Improvement in the depth of response with novel combinations has resulted in a near doubling of the overall survival (OS) among patients with multiple myeloma (MM) [1,2]. Several new agents, including the third-generation immunomodulatory agent (IMiD) -pomalidomide, the second-generation proteasome inhibitors (PIs) -carfilzomib and ixazomib, the histone deacetylaste inhibitor -panobinostat, and two monoclonal antibodies -elotuzumab and daratumumab, have all been recently approved. The multitude of novel agents and combinations, however, has resulted in somewhat of a conundrum for physicians who manage myeloma patients -how do we incorporate these new treatments into clinical practice? While there is no ideal sequence of therapy for every patient, there are several nuances worthy of discussion to help clarify the therapeutic options for each stage of treatment. Goals of treatmentThe evaluation of agents in novel combinations has shown the importance of depth of response, consistently correlating with higher complete remission (CR) rates and progression-free survival (PFS). It is now possible to achieve a high level of tumor burden reduction leading to negative minimal residual disease, an important goal in the treatment of myeloma that is associated with prolonged PFS and possibly longer OS [3,4]. This information reinforces the objective that while antimyeloma therapy should be chosen carefully for every individual patient based on disease characteristics, age, frailty and co-morbidities, the primary goal of therapy is to improve OS. Induction therapyThe approach to the treatment of newly diagnosed MM has more recently centered around two questions: doublet or triplet drug combinations; and upfront or delayed autologous stem-cell transplant (ASCT). The SWOG S0777 study demonstrated the importance of adding bortezomib to lenalidomide and dexamethasone (RVD) as a triplet combination when compared with the doublet combination of lenalidomide and dexamethasone alone (Rd) [5]. The use of RVD showed an improvement in overall response rates (ORR: 82 vs 72%), median PFS (55 vs 43 months; p = 0.0037) and OS (75 vs 64 months; p = 0.25) in those patients receiving the triplet compared with those in the doublet arm. The Integroupe Francophone du Myeloma (IFM) 2013-04 study showed the superiority of a PI/IMiD combination when bortezomib/thalidomide/dexamethasone (VTD) was compared with bortezomib/cyclophosphamide/dexamethasone (VCD) and found to be superior with an overall response rate in the VTD arm of 92.3 versus 83.4% in the VCD arm [6]. Based on response rates, depth of response and PFS as surrogate markers for outcome, three-drug combinations including an IMiD, PI and dexamethasone are currently the standard of care for induction. High-dose therapy & ASCTDespite improved induction strategies, ASCT remains the standard of care in eligible patients. This was confirmed by the recently published trial by the IFM in whi...

BC094916 suppressed SP 2/0 xenograft tumor by down-regulating Creb1 and Bcl2 transcription

“…Targeted therapies, such as treatment with the BRAF inhibitor vemurafenib in BRAF-mutated MM patients or BCL-2 inhibition with venetoclax for MM with t [ 4 , 14 ] are currently being used for treatment of relapsed and refractory MM (RRMM) [ 15 ]. Even with recent advances in therapy regimen, MM patients commonly develop drug resistance and relapse [ 30 , 31 ]. To explore novel therapies that target plasma cells to treat autoimmune diseases and MM, BC094916 was overexpressed in SP 2/0 cells (Fig.…”

Sensitive intranuclear flow cytometric quantification of IRF4 protein in multiple myeloma and normal human hematopoietic cells

“…Another minor limitation of this protocol is that it is currently only compatible with flow cytometric analysis, and no sorting protocols have yet been established to isolate IRF4-positive cells for downstream functional or RNA analyses due to the necessary fixation and permeabilization steps. In addition, as new immunotherapy-based strategies continue to emerge for the treatment of MM ( Costello, 2017 ; Costello and Mikhael, 2018 ; Siegel et al., 2020 ), flow cytometry studies that rely on cell surface marker analysis of specific subpopulations of MM cells may become more challenging to interpret. We have noted one example of a situation in which it was not possible to analyze the IRF4 MFI within a CD38-positive population due to a lack of CD38-immunoreactive cells, which is likely related to that patient’s treatment status of active anti-CD38 monoclonal antibody therapy.…”

Selective antisense oligonucleotide inhibition of human IRF4 prevents malignant myeloma regeneration via cell cycle disruption

“…Characterized by abnormal expansion of malignant clonal progenitors and their immature antibody-producing plasma cell progeny, MM generally recurs and is refractory to further treatment within 5 years. Despite a plethora of novel therapies (Costello and Mikhael, 2018;Kumar et al, 2019;Stewart et al, 2015), treatment toxicities have presented new challenges for patients and clinicians (Paner et al, 2018). Moreover, disease relapse rates remain high, in part due to acquisition of drug resistance (Siegel et al, 2020), along with malignant regeneration of MM cells in inflammatory microenvironments (Bianchi and Ghobrial, 2014;Yaccoby, 2018).…”